AUTHOR=Knutsen Russell H. , Gober Leah M. , Kronquist Elise K. , Kaur Maninder , Donahue Danielle R. , Springer Danielle , Yu Zu Xi , Chen Marcus Y. , Fu Yi-Ping , Choobdar Feri , Nguyen My-Le , Osgood Sharon , Freeman Joy L. , Raja Neelam , Levin Mark D. , Kozel Beth A. 

TITLE=Elastin Insufficiency Confers Proximal and Distal Pulmonary Vasculopathy in Mice, Partially Remedied by the KATP Channel Opener Minoxidil: Considerations and Cautions for the Treatment of People With Williams-Beuren Syndrome

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.886813

DOI=10.3389/fcvm.2022.886813

ISSN=2297-055X

ABSTRACT=<sec><title>Background</title><p>Williams Beuren syndrome (WBS) is a recurrent microdeletion disorder that removes one copy of elastin (<italic>ELN</italic>), resulting in large artery vasculopathy. Early stenosis of the pulmonary vascular tree is common, but few data are available on longer-term implications of the condition.</p></sec><sec><title>Methods</title><p>Computed tomography (CT) angiogram (<italic>n</italic> = 11) and echocardiogram (<italic>n</italic> = 20) were performed in children with WBS aged 3.4–17.8 years. Controls (<italic>n</italic> = 11, aged 4.4–16.8 years) also underwent echocardiogram. <italic>Eln</italic><sup>+/−</sup> mice were analyzed by invasive catheter, echocardiogram, micro-CT (μCT), histology, and pressure myography. We subsequently tested whether minoxidil resulted in improved pulmonary vascular endpoints.</p></sec><sec><title>Results</title><p>WBS participants with a history of main or branch pulmonary artery (PA) stenosis requiring intervention continued to exhibit increased right ventricular systolic pressure (RVSP, echocardiogram) relative to their peers without intervention (<italic>p</italic> &lt; 0.01), with no clear difference in PA size. Untreated <italic>Eln</italic><sup>+/−</sup> mice also show elevated RVSP by invasive catheterization (<italic>p</italic> &lt; 0.0001), increased normalized right heart mass (<italic>p</italic> &lt; 0.01) and reduced caliber branch PAs by pressure myography (<italic>p</italic> &lt; 0.0001). <italic>Eln</italic><sup>+/−</sup> main PA medias are thickened histologically relative to <italic>Eln</italic><sup>+/+</sup> (<italic>p</italic> &lt; 0.0001). Most <italic>Eln</italic><sup>+/−</sup> phenotypes are shared by both sexes, but PA medial thickness is substantially greater in <italic>Eln</italic><sup>+/−</sup> males (<italic>p</italic> &lt; 0.001). <italic>Eln</italic><sup>+/−</sup> mice showed more acute proximal branching angles (<italic>p</italic> &lt; 0.0001) and longer vascular segment lengths (<italic>p</italic> &lt; 0.0001) (μCT), with genotype differences emerging by P7. Diminished PA acceleration time (<italic>p</italic> &lt; 0.001) and systolic notching (<italic>p</italic> &lt; 0.0001) were also observed in <italic>Eln</italic><sup>+/−</sup> echocardiography. Vascular casting plus μCT revealed longer generation-specific PA arcade length (<italic>p</italic> &lt; 0.0001), with increased PA branching detectable by P90 (<italic>p</italic> &lt; 0.0001). Post-weaning minoxidil decreased RVSP (<italic>p</italic> &lt; 0.01) and normalized PA caliber (<italic>p</italic> &lt; 0.0001) but not early-onset proximal branching angle or segment length, nor later-developing peripheral branch number.</p></sec><sec><title>Conclusions</title><p>Vascular deficiencies beyond arterial caliber persist in individuals with WBS who have undergone PA stenosis intervention. Evaluation of <italic>Eln</italic><sup>+/−</sup> mice reveals complex vascular changes that affect the proximal and distal vasculatures. Minoxidil, given post-weaning, decreases RVSP and improves lumen diameter, but does not alter other earlier-onset vascular patterns. Our data suggest additional therapies including minoxidil could be a useful adjunct to surgical therapy, and future trials should be considered.</p></sec>